Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:46][C:18]2[N:19]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)[C:20](=[O:30])[N:21]([CH2:24][C:25]3([CH3:29])[CH2:28][O:27][CH2:26]3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:46][C:18]2[N:19]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)[C:20](=[O:30])[N:21]([CH2:24][C:25]3([CH3:29])[CH2:26][O:27][CH2:28]3)[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC3(C)COC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC3(C)COC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.81 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[(3-methyloxetan-3-yl)methyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (40 mL), N,N′-carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.44 g, 57%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].Cl.[NH2:20][CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)CC)C>C1COCC1>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:16])([CH3:15])[O:14][B:10]([C:7]2[CH:8]=[CH:9][C:4]([NH:1][C:2](=[O:3])[NH:20][CH2:21][C:22]([NH2:24])=[O:23])=[CH:5][CH:6]=2)[O:11]1
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)NCC(N)=O)cc2)OC1(C)C
Yield: 88.5 %

Procedure:
2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.22 mmol) was dissolved in dry THF and stirred with 2-aminoacetamide hydrochloride (108 mg, 1.46 mmol) and triethylamine (drops) at 60° C. overnight. The mixture was reduced in vacuo, yielding the title compound (345 mg, 1.08 mmol, 88%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[OH:19].[Na+].C(OCC)(=O)C>S(=O)(=O)(O)O.O1CCCC1.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]=[C:9]([C:12](=[O:19])[CH3:13])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC=C(C#C[Si](C)(C)C)C1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC=C(C(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-allyloxycarbonyl-3-trimethylsilylethynyl-3-pyrroline (7.60 g), mercuric sulfate (0.9 g) and sulfuric acid (5 drops) in a mixture of tetrahydrofuran (76 ml) and water (23 ml) was stirred at room temperature overnight. After confirming the disappearance of the starting material, to the mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate twice, and the combined organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine successively, dried over magnesium sulfate. Evaporation of the solvent gave 1-allyloxycarbonyl-3-acetyl-3-pyrroline (2.3 g).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:24]3[CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22][CH2:23]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.9 %

Procedure:
To a mixed solution of a commercially available product of 1-(diphenylmethyl)azetidin-3-one (10.1 g, 42.6 mmol), TH-IF (100 mL) and acetic acid (5.00 mL) was added ethylpiperazine (6.48 mL, 51.1 mmol) at room temperature. The resultant mixture was stirred at room temperature for 45 minutes. Sodium triacetoxyborohydride (18.1 g, 85.1 mmol) was added to the reaction mixture at room temperature and then stirred at room temperature for 15 hours. Sodium hydrogen carbonate and water were added to the reaction mixture, and the resultant solution was then extracted with ethyl acetate. An organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (ethyl acetate-methanol) and was then further purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1 and the 1:1) to give the title compound (12.7 g, yield: 89%).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[CH:12]=[O:13]>O.CC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:12]([OH:2])=[O:13]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Yield: 71.6 %

Procedure:
To a solution of potassium permanganate (3.05 g) in water (100 ml) was added to a solution of 3,4-dimethoxy-5-nitrobenzaldehyde (2.7 g) in acetone (80 ml). The mixture was then stirred at 20° for 18h whereupon the acetone was evaporated and the residue acidified (2N HCl) and was then decolourised by the addition of sodium metabisulphite sodium. The mixture was then extracted with ethyl acetate (3×200 ml) and the dried extracts evaporated to give the title compound as a colourless solid (2.08 g) m.p. 197°-198°.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].Br[C:13](C)(C)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(C(C)C)CC)(C)C>>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][NH:4][C:3]1[C:2]([CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1c(C)cccc1[N+](=O)[O-]

Procedure:
A mixture of 2-methyl-6-nitroaniline (XIV, 2.00 g), ethyl bromoacetate (III, 3.5 ml) and diisopropylethylamine (3.5 ml) is heated at reflux (140°) for 8 hr. The resultant solution is allowed to cool to 20°-25°. After dilution with aqueous sodium bicarbonate, extraction several times with ethyl acetate, drying with magnesium sulfate and concentration the residue is resubmitted to the above reaction conditions for an additional 16 hr. After workup, purification by flash chromatography eluting with a gradient of hexane/ethyl acetate (10/1Γ5/1), pooling and concentrating the appropriate fractions, the title compound is obtained, mp 49°-52°; IR (mineral oil) 3365, 2953, 2925, 1731, 1536, 1475, 1461, 1374, 1344, 1236, 1207, 1104 and 1022 cm-1 ; NMR (CDCl3) 7.88, 7.33, 6.8-7.0, 6.86, 4.17, 3.94, 2.39 and 1.23 δ.
Reaction SMILES: [CH:1]1([C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])CCCC[CH2:2]1.N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1.[Cl:35]CCC(Cl)=O>>[Cl:35][CH2:2][CH2:1][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(Cl)CCCl
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)CCCl
Yield: 98 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 300 mg, 1.51 mmol) and 3-chloropropanoyl chloride (189 μL, 1.97 mmol) were converted to the title compound (430 mg, 98%). 1H NMR (DMSO-d6) δ 8.16 (d, J=8.1 Hz, 1H), 7.66-7.63 (m, 2H), 7.22 (s, 2H), 4.18 (t, J=8.6 Hz, 2H), 3.89-3.86 (m, 2H), 3.21 (t, J=8.5 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H); MS (ESI+) m/z 289.2 (M+H)+.
Reaction SMILES: BrC1C=CC=C2C=1[N:9]([S:11](C1C=CC(OC)=CC=1)(=[O:13])=[O:12])CC2.[Br:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2C=1N[CH:29]=[CH:28]2.[C:32]([BH3-])#[N:33].[Na+].[OH-].[Na+]>C(O)(=O)C>[Br:22][CH:23]1[CH2:24][C:25]2[C:32](=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:33]1[S:11]([NH2:9])(=[O:13])=[O:12]
Reactant: Brc1cccc2cc[nH]c12
Reactant: [BH3-]C#N
Reactant: COc1ccc(S(=O)(=O)N2CCc3cccc(Br)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NS(=O)(=O)N1c2ccccc2CC1Br
Yield: 87 %

Procedure:
7-Bromo-1-(4-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole (11 in scheme 2 wherein R2═OCH3): A solution of 7-bromo-1H-indole (0.30 g, 1.53 mmol) in glacial acetic acid (1.5 mL) was treated with sodium cyanoborohydride (0.14 g, 2.29 mmol) under N2 at 0° C. After aqueous sodium hydroxide solution was added to quench excess acid, the resulting mixture was then extracted with CH2Cl2 (20 mL×3). The combined organic layers were dried over MgSO4, the dried solution was filtered, and the filtrate was concentrated. The residue was dissolved in pyridine and 4-methoxyphenylsulfonyl chloride was added. The reaction mixture was refluxed overnight. The solvent was removed and the residue was purified by flash chromatography (EtOAc: n-hexane=1:2) to afford 11 (370.6 mg, 87%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:26][C@H:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH3:25])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 47.3 %

Procedure:
2.4 g of 2,4,6-trichloropyrimidine was dissolved in 24 ml of tetrahydrofuran, and 2.0 ml of triethylamine was added at room temperature, and a solution of 2.0 g of (S)-(−)-1-(4-fluorophenyl)ethylamine in 12 mL of tetrahydrofuran was added dropwise, and then the mixture was stirred at room temperature for 9.5 hours. The reaction mixture was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 1.77 g of the objective compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][OH:36])=[CH:33][CH:32]=1.O>CN(C)C=O>[N:13]1([C:4]2[N:3]=[C:2]([O:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:32][CH:33]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: OCc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of ethyl 4-chloro-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (520 mg, 1.72 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (829 mg, 6 mmol) and 4-(trifluoromethoxy)benzyl alcohol (384 mg, 2 mmol) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was allowed to cool to room temperature and water was added, which was followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was applied to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1) to give the title compound (420 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9][N:8]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]2=[N:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1n[nH]c2ncc(Br)cc12
Solvent: ClCCl
Product: COC(=O)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (2.92 Kg, 11.4 mol) in anhydrous DCM (88 L) was added TEA (2.38 L, 17.1 mol). The solution was cooled to 0° C. before adding dropwise a solution of TrCl (4.0 Kg, 14.3 mol) in anhydrous DCM (51 L). The solution was warmed to room temperature and stirred for 20 hours. The reaction was then washed once with water (29 L), once with aqueous 25% NaCl (29 L), dried over Na2SO4 and concentrated to a volume of 3.0 L to give methyl 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XXII) (5.69 Kg, 11.4 mol, 77.3% purity, 99.5% assay yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm 3.91 (s, 3H), 7.19 (d, J=8.4 Hz, 5H), 7.21-7.32 (m, 10H), 8.45 (d, J=2.4 Hz, 1H), 8.61 (d, J=2 Hz, 1H); ESIMS found C27H20BrN3O2 m/z 520.0 (M+Na).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[O:19]1[C:23]2=[CH:24][CH:25]=[CH:26][C:27]([NH2:28])=[C:22]2[N:21]=[CH:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([NH:28][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[C:22]=2[N:21]=[CH:20]1
Reactant: Nc1cccc2ocnc12
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2ocnc12
Yield: 54.6 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 268 mg of 1,3-benzoxazol-4-amine in place of the 2,4-difluoroaniline. 193 mg of N-(1,3-benzoxazol-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of an ecru solid, the characteristics of which are the following:
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.O>CS(C)=O>[Cl:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[C:17]=1[N:23]1[CH2:28][CH2:27][N:26]([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:25][CH2:24]1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: Clc1cccc(Cl)c1N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(N3CCN(c4c(Cl)cccc4Cl)CC3)[nH]c2c1
Temperature: 25 °C

Procedure:
A mixture of the benzoimidazole from step (c) above (75 mg, 0.34 mmol), the piperazine from step (a) above (90 mg, 0.39 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.58 mmol, Aldrich) in DMSO (2 mL) was stirred at 80° C. for 24 h. The mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (2×10 mL) and brine (5 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexane to give the title compound as a white solid. M.p. 263-265° C. MS (ESI, pos. ion) m/z: 415 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[C:10]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:6]=1[F:16])[CH3:2].[OH:18]OS([O-])=O.[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH2:33]>CO>[CH3:14][C:12]([S:11]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:16])[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:17])(=[O:18])=[O:33])([CH3:13])[CH3:15]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CCNC(=O)c1c(F)cccc1SC(C)(C)C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)c1c(F)cccc1S(=O)(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
A 0° C. solution of N-ethyl 2-fluoro-6-(1,1-dimethylethylthio)benzamide, described in Example 194, (0.15 g, 0.59 mmol) in methanol (5 mL) was combined with a 0° C. solution of OXONE® (1.08 g, 1.76 mmol) in water (5 mL). This mixture was stirred overnight, then was poured into 25% aq sodium metabisulfite (100 mL) and extracted with ether (3×100 mL). The combined organics were washed with brine followed with water, then was dried (MgSO4) and concentrated to give the title compound as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[CH3:1][O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(C)(C)OC(=O)C1CCC(C(=O)O)CC1
Reactant: CCOC(C)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCC(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cyclohexane-1,4-dicarboxylic acid mono-t-butyl ester (26.9 mmol, 5.0 g) and N,N′-carbonyldiimidazole (33.6 mmol, 5.44 g) in anhydrous THF (80 mL) were stirred 16 h at room temperature under argon. In a separate, sealed and argon-flushed flask, LiHMDS (1.0 M in THF, 56.5 ml) was added to 40 mL anhydrous THF stirring at −78° C. To this solution was added dropwise anhydrous ethyl acetate (57.8 mmol, 5.65 mL). This solution was allowed to stir at −78° C. for 1 hour prior to dropwise addition of original CDI/acid solution that had been stirring overnight. The reaction mixture was allowed to stir and warm to room temperature overnight. The reaction was then quenched with saturated NH4Cl(aq) (200 mL) and extracted with Et2O (100×2). The combined organics were then washed with water, saturated brine, and dried over Na2SO4. The solvent was removed in vacuo and the crude residue (8.5 g) was used in the next step without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[ClH:31].[CH2:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:32][CH:33]=1)[CH2:22][CH2:23][CH3:24]
Reactant: NCCCSc1ccncc1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 72.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 0.93 ml (4.96 mmol) of 4-n-butylbenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minute. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.10 g of the desired compound (free base) (80.7% colorless wax), mp: 46.0°-47.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>[H][H].[Pd]>[C:13]1([C:8]2[C:7]3[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=3)[NH:10][N:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: [Pd]
Product: Nc1ccc2c(-c3ccccc3)n[nH]c2c1
Yield: 71.5 %

Procedure:
To a solution of 2-chloro-5-nitro-benzophenone(1.0 g) in THF (tetrahydrofuran) (15 ml) was added anhydrous hydrazine(120 mg). The resulting reaction mixture was kept stirring at room temperature for 2-4 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc, washed with water and brine, dried over Na2SO4. Removal of the solvent afforded (0.8 g, 88%) product 6-Nitro-3-phenyl-1H-indazole(5). 6-Nitro-3-phenyl-1H-indazole was hydrogenated over H2/Pd and gave 0.5 9 of 3-phenyl-1H-indazol-6-ylamine (71.5%). M/z: 210.0. 1H NMR(CD3OD): 7.86(d, 2H, J=7.9 Hz), 7.47( t, J=8.1 Hz), 7.35(t, 3H, J=8.7 Hz), 7.01 (d, 1H, J=8.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:12][NH:13][CH3:14].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([N:13]([CH3:14])[CH3:12])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1I
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (1.16 g, 3.06 mmol) was added to a solution of 5-bromo-2-iodo-benzoic acid (1.00 g, 3.06 mmol), dimethyl amine (2 M in THF, 3.06 ml, 3.06 mmol) and di-iso-propyl ethyl amine (1.59 ml, 9.18 mmol) in N,N-Dimethylformamide (12 ml). The reaction was stirred at room temperature overnight. Ethyl acetate was added and the mixture was washed with water, the organic layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography to yield 5-bromo-2-iodo-N,N-dimethyl-benzamide as a white solid. (0.96 g, 90%). MS: m/z 328.1 (M+H+).